IL-17A in Asthma - A Question of Severity

Ian P Lewkowich

doi:10.4172/2155-9899.1000107

Abstract

Allergic asthma is a chronic inflammatory disease of the lung driven by aberrant responses to normally innocuous environmental allergens. Disease is characterized by excessive IgE synthesis, eosinophilic pulmonary inflammation, mucus hypersecretion, and airway remodeling, and airway hyperresponsiveness - all leading to the clinical features of disease - reversible episodes of coughing, shortness of breath and wheezing. While the excessive production of cytokines like IL-4, IL-5 and IL-13 by allergen specific-Th2 cells is sufficient to explain most features of allergic asthma, increasing evidence suggests that the Th2 paradigm does not explain the full spectrum of disease severity. In particular, severe asthmatics represent a small subset of asthmatics, in which disease is associated with more severe airway reactivity, a mixed eosinophilic/neutrophilic infiltrate, and insensitivity to treatment with corticosteroids. Thus, severe asthmatics are not only more susceptible asthma-related complications; they are underserved by currently available therapies. Recent evidence suggests that the development of severe disease may be associated with the development of a mixed Th2/Th17 response. Herein, we will assess the data from human and animal models suggesting a link between a mixed Th2/Th17 response, and the development of severe asthma. A greater understanding of the mechanisms responsible for the development of severe asthma may allow the development of efficacious therapeutics for the treatment of this intractable form of disease.

Highlights

Allergic asthma is a chronic inflammatory disease of the lung driven by aberrant responses to normally innocuous environmental allergens
Rather than the predominant eosinophilia observed in patients with mild asthma, allergic inflammation in severe asthmatics is often neutrophilic in nature, and the degree of neutrophilia correlates with disease severity [8,9,10,11]
We have demonstrated that following inhalation of house dust mite (HDM), a common human aeroallergen, we observe differential development of Th17 responses, in mice on different genetic backgrounds [53]

Summary

Allergic Asthma

Allergic asthma is a chronic inflammatory disease of the lung caused by excessive immune responses to normally innocuous environmental allergens. To better address the roles of IL-17A in the development of allergic asthma, some studies have compared the development of asthma in mice lacking IL-17A Both C57Bl/6 and BALB/c Il17a -/mice demonstrated significantly reduced pulmonary eosinophilia, less robust Th2 cytokine production by spleen or lung cells, and decreased IgE levels following OVA alum sensitization and intranasal OVA challenge [54,55]. While these studies are difficult to reconcile with the studies arguing for a pathogenic role for IL-17A, a recent report by Besnard et al suggests that the presence of IL-22 (another Th17-derived cytokine) may influence the ability of IL-17A to promote protective versus pathogenic responses in the lung They demonstrate that blockade of IL-17A in Il22 -/- mice significantly enhanced eosinophilic inflammation and Th2 cytokine production, while IL-17A blockade in control mice had the opposite effect [57]. The relative production of IL-22 and IL-17A in these models and in humans with mild versus severe asthma is a question that warrants further investigation

Mucin production

Findings

Conclusions